Currently, pharmacotherapy of HIV infections is mainly carried out through a highly active anti-retroviral therapy (HAART), which is a multi-drug therapy employing a plurality of drugs in combination. HAART, however, has a downside in that replacement of one or more constituent drugs is unavoidable if and when a drug-resistant virus emerges or adverse side effects are observed. In order to solve this problem, a new active ingredient, 4′-ethynyl-2′,3′-didehydro-3′-deoxythymidine (i.e., 4′-ethynyl d4T) was previously developed (see Patent Document 1). The compound 4′-ethynyl d4T is effective on multi-drug resistant virus and is considered to have low mitochondrial toxicity (i.e., high safety). From these points, this compound is expected to ensure long-term administration and maintenance of adherence.
In one known method for producing 4′-ethynyl d4T, thymidine or uridine is employed as a synthesis starting material (see Patent Document 1 and Non-Patent Document 1). This synthesis method, employing such a natural starting material, requires a number of synthesis steps, thereby elevates the production cost. Thus, the method is not suited for large-scale production, which is problematic.
In recent years, in order to overcome the drawback, another method for synthesizing 4′-ethynyl d4T employing inexpensive furfuryl alcohol serving as a starting material was developed, and this method requires relatively a small number of steps (see Patent Document 2). In this method, when a Lewis acid is used, α-form and β-form (43:53) are formed in the step of glycosylation (thymination) of a dihydrofuran compound. Thus, a subsequent separation/purification step considerably degrades the target yield, making the synthesis method unsuitable for mass production.
Meanwhile, in another known method for synthesizing a β-glycoside compound from a dihydrofuran compound, a palladium reagent is employed as a catalyst (see, for example, Non-Patent Document 2). Non-Patent Document 2 discloses that the method employs an achiral phosphine ligand and an α-β-mixed form dihydrofuran compound serving as a starting material, to thereby yield a product of an α-β-mixed form. The document also discloses that, when an optically active Trost ligand is used, only a β-glycoside compound is produced, and the starting α-form material is recovered. This clearly indicates that an α-form product is yielded from an α-form starting material, and a β-form product is yielded from a β-form starting material.
Through the aforementioned methods, a β-form-pure dihydrofuran compound must be synthesized and provided for attaining high-yield glycosylation.
Generally, methods for synthesizing a dihydrofuran compound are disclosed by several documents. In one disclosed method, a dihydrofurandiol compound corresponding to the target and serving as a starting material is diacetylized (see Patent Document 2). However, when the method is employed, the produced dihydrofuran compound has an α-β-mixed form (α:β or β:α=21:79), and no β-form-pure product is yielded.
There has also been reported a method for synthesizing a dihydrofuran compound in which a dihydrofurandiol compound having an asymmetric substituent serving as a starting material is silylated. However, the yielded dihydrofuran compound has an α-β-mixed form (α:β or β:α=80:20) (see Non-Patent Document 3).
Also known is a similar synthesis method in which a corresponding lactone is reduced and then acetylated. However, the yielded dihydrofuran compound has an β-β-mixed form (α:β=1:1) (see Non-Patent Document 2).
In the synthesis of a tetrahydrofuran compound, β-form-selective synthesis is known to be difficult. In one case, the 1-position ol and the 5-position ol of a tetrahydrofuranthiol compound are modified by two steps. However, the product is indicated to have an α-β-mixed form (Non-Patent Document 4).
Through synthesis of a tetrahydrofuran compound from glyceraldehyde, the product is indicated to have an β-β-mixed form (α:β=2:1) (Non-Patent Document 5).
As described above, those skilled in the art know that difficulty is encountered in selectively yielding a β-dihydrofuran compound, a β-tetrahydrofuran compound, and a β-glycoside compound.